Primary Objective- Evaluate longitudinal intra-individual and inter-individual variability of PBMC biomarkers in healthy participants:o LRRK2 protein (pg/mL)o total protein (ug/mL)o pS935 LRRK2/total LRRK2 peptide ratioo pRab10/Rab10 peptide ratio…
ID
Source
Brief title
Condition
- Movement disorders (incl parkinsonism)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The endpoints include total LRRK2 protein, pS935 LRRK2 protein, and
pRab10/Rab10 levels measured in PBMCs.
Secondary outcome
• LRRK2 protein in CSF
Background summary
Parkinson*s disease (PD) is a common neurodegenerative disease, affecting
approximately 1-2% of persons aged >= 65 years. Mutations in the leucine-rich
repeat kinase 2 (LRRK2) gene are an established risk factor for PD, linked to
approximately 5% of familial PD and 1-2% of sporadic PD cases. While the exact
pathophysiological mechanisms are not completely understood, the associated
mutations cause an increase in LRRK2 kinase activity, which leads to lysosomal
dysfunction. It is hypothesized that lysosomal dysfunction can be an important
mechanism for accumulation of intracellular protein such as alpha-synuclein,
which is a hallmark of PD pathophysiology. In recent years, multiple studies
have aimed to inhibit LRRK2 kinase as a potential disease-modifying therapy for
PD by restoring lysosomal function. As an alternative, human genetic data and
results from preclinical studies suggest that reducing LRRK2 protein in the
brain may be an effective approach for the treatment of PD. A non-coding
variant within the LRRK2 locus, SNP rs76904798, increases LRRK2 expression in
microglia and is associated with increased risk for developing PD; The
protective LRRK2 haplotype, N551K-R1398H-K1423K, is associated with reduced
LRRK2 levels; reduction of LRRK2 in brain is protective in mouse models of PD.
To quantify the effect of these novel therapeutic interventions aimed at
reducing LRRK2 protein levels, it is necessary to qualify methods that will
allow measurement of total LRRK2 protein, phosphorylated LRRK2, and substrates
of LRRK2. The latter includes a group of Rab guanosine triphosphates (GTPases)
that regulate intracellular trafficking. One of the GTPases that will be
investigated in the present study is Rab10, which is phosphorylated by LRRK2
and may act as a key marker of LRRK2 downregulation.
This observational study is designed to evaluate the longitudinal variability
of LRRK2 biomarkers in samples collected over 2 weeks to support the
development of novel therapeutic interventions. Understanding the longitudinal
variability of these biomarkers over this 2-week timeframe is key in the
evaluation of novel LRRK2 therapeutics with a durable pharmacodynamic response.
This study will assess variability in healthy participants of LRRK2 and pS935
LRRK2 protein levels and phosphorylation levels of the LRRK2 substrate Rab10
from day-to-day, within-day and between individuals. Additionally, preclinical
data demonstrate that CSF LRRK2 can be used as surrogate biomarker for
monitoring LRRK2 reductions in brain tissue. Therefore, LRRK2 protein levels
will be measured at two timepoints 24 hours apart to evaluate longitudinal
variability and to explore the correlation between CSF and Peripheral Blood
Mononuclear Cells (PBMC)/whole blood LRRK2 levels. CSF will be collected for
measurements in 3 different assays and to investigate the stability of LRRK2 in
CSF over time and to confirm the robustness of the assay of CSF in a clinical
trial setting.
Study objective
Primary Objective
- Evaluate longitudinal intra-individual and inter-individual variability of
PBMC biomarkers in healthy participants:
o LRRK2 protein (pg/mL)
o total protein (ug/mL)
o pS935 LRRK2/total LRRK2 peptide ratio
o pRab10/Rab10 peptide ratio
Secondary Objective
- Evaluate longitudinal intra-individual and inter-individual variability of
CSF LRRK2 and correlation of LRRK2 measurement in 3 different assays in healthy
participants:
o LRRK2 protein (pg/mL) as measured by SISCAPA assay
o LRRK2 protein (pg/mL) as measured by mid-domain SIMOA assay
o LRRK2 protein (pg/mL) as measured by N-terminal SIMOA assay
Study design
This is a prospective, single-centre, methodology biomarker study in healthy
participants. Randomisation is not applicable. Please see Part 3 of the
Clinical Protocol.
Study burden and risks
This is a non-interventional biomarker study. No investigational drug will be
administered. Sampling of the biomarkers will be done via blood sampling and
CSF sampling. All collections will be performed in a state-of-the-art clinical
research unit and will be medically supervised by qualified medical staff. The
blood sampling and CSF sampling are considered low risk procedures and the
burden for the participants related to the study procedures will be kept to a
minimum.
5 science Park 395 Winchester Avenue
New Haven CT 06511
US
5 science Park 395 Winchester Avenue
New Haven CT 06511
US
Listed location countries
Age
Inclusion criteria
1. 18 - 70 years of age at screening (inclusive).
2. BMI in the range of 18 - 30 kg/m2, inclusive at screening and with a minimum
weight of 50 kg.
3. Able to speak, read, and understand study procedures in Dutch sufficiently
to allow completion of all study assessments.
4. Must understand and provide written informed consent prior to the initiation
of any protocol-specific procedures.
5. Women of childbearing potential must use a form of birth control (e.g., oral
contraceptive, condom use, IUD, abstinence of heterosexual intercourse) during
the study.
Exclusion criteria
1. Evidence of any active or chronic disease or condition that could interfere
with, or for which the treatment might interfere with, the conduct of the
study, or that would pose an unacceptable risk to the participant in the
opinion of the investigator (following a detailed medical history, physical
examination, vital signs (systolic and diastolic blood pressure, pulse rate,
body temperature) and 12-lead electrocardiogram (ECG)). Minor deviations from
the normal range may be accepted, if judged by the Investigator to have no
clinical relevance.
5. Abnormal findings in the resting ECG at screening defined as:
- QTcF longer than 450 or shorter than 350 msec for men and QTcF longer then
470 or shorter then 360 msec for women
- Notable resting bradycardia (HR under 40 bpm) or tachycardia (HR over 100 bpm)
- Other abnormal findings in the resting ECG as determined by the investigator
8. Use of any medications (prescription or over-the-counter [OTC] including
herbal medication), within 14 days prior to the first blood collection on day
1, or less than 5 half-lives (whichever is longer), except for birth control,
paracetamol (up to 4 g/day), and ibuprofen (up to 1g/day). Other exceptions
will only be made if the rationale is clearly documented by the investigator.
18. For CSF sampling, any of the criteria below:
- History of clinically significant hypersensitivity to local anaesthetics that
may be used for LP (e.g., lidocaine).
- Criteria that would preclude an LP, such as a local infection at the site of
the LP, less then 100x 103/µl platelet count at screening or clinically
significant coagulation abnormality or significant active bleeding, or
treatment with an anticoagulant or treatment with more than 2 antiplatelet
agents.
- History of clinically significant back pathology and/or back injury (e.g.,
degenerative disease, spinal deformity, or spinal surgery) that may predispose
to complications or technical difficulty with LP.
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL84388.056.23 |